Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

Yeming Wang, Fei Zhou, Dingyu Zhang, Jianping Zhao, Ronghui Du, Yi Hu, Zhenshun Cheng, Ling Gao, Yang Jin, Guangwei Luo, Shouzhi Fu, Qiaofa Lu, Guanhua Du, Ke Wang, Yang Lu, Guohui Fan, Yi Zhang, Ying Liu, Shunan Ruan, Wen Liu, Thomas Jaki, Frederick G Hayden, Peter W Horby, Bin Cao, Chen Wang, Yeming Wang, Fei Zhou, Dingyu Zhang, Jianping Zhao, Ronghui Du, Yi Hu, Zhenshun Cheng, Ling Gao, Yang Jin, Guangwei Luo, Shouzhi Fu, Qiaofa Lu, Guanhua Du, Ke Wang, Yang Lu, Guohui Fan, Yi Zhang, Ying Liu, Shunan Ruan, Wen Liu, Thomas Jaki, Frederick G Hayden, Peter W Horby, Bin Cao, Chen Wang

Abstract

Background: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19.

Methods: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed.

Discussion: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020.

Trial registration: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.

Keywords: Administrative information; Antiviral; COVID-19; China; Clinical trial; Remdesivir.

References

    1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733. doi: 10.1056/NEJMoa2001017.
    1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5.
    1. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513. doi: 10.1016/S0140-6736(20)30211-7.
    1. Wang Dawei, Hu Bo, Hu Chang, Zhu Fangfang, Liu Xing, Zhang Jing, Wang Binbin, Xiang Hui, Cheng Zhenshun, Xiong Yong, Zhao Yan, Li Yirong, Wang Xinghuan, Peng Zhiyong. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061. doi: 10.1001/jama.2020.1585.
    1. Lo MK, Jordan R, Arvey A, et al. GS-5734 and its parent nucleoside analog inhibit filo-, pneumo-, and paramyxoviruses. Sci Rep. 2017;7:43395. doi: 10.1038/srep43395.
    1. WHO . WHO R&D blueprint: informal consultation on prioritization of candidate therapeutic agents for use in novel coronavirus 2019 infection. Geneva: WHO; 2020.
    1. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381–385. doi: 10.1038/nature17180.
    1. Jordan PC, Liu C, Raynaud P, et al. Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase. PLoS Pathog. 2018;14(2):e1006889. doi: 10.1371/journal.ppat.1006889.
    1. Tchesnokov EP, Feng JY, Porter DP, Gotte M. Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir. Viruses. 2019;11(4):E326. doi: 10.3390/v11040326.
    1. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396):eaal3653. doi: 10.1126/scitranslmed.aal3653.
    1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–271. doi: 10.1038/s41422-020-0282-0.
    1. Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antivir Res. 2019;169:104541. doi: 10.1016/j.antiviral.2019.104541.
    1. de Wit E, Feldmann F, Cronina J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020;117(12):6771–6776. doi: 10.1073/pnas.1922083117.
    1. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. doi: 10.1038/s41467-019-13940-6.
    1. Mulangu S, Dodd LE, Davey RT, Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293–2303. doi: 10.1056/NEJMoa1910993.
    1. Whitehead J, Stratton I. Group sequential clinical trials with triangular continuation regions. Biometrics. 1983;39(1):227–236. doi: 10.2307/2530822.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. J Pharmacol Pharmacother. 2010;1(2):100–107. doi: 10.4103/0976-500X.72352.
    1. Dimairo M, Coates E, Pallmann P, et al. Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design. BMC Med. 2018;16(1):210. doi: 10.1186/s12916-018-1196-2.
    1. Whitehead J. The design and analysis of sequential clinical trials. 2. Chichester: Wiley; 1997.
    1. World Health Organization . Ethics in epidemics, emergencies and disasters: research, surveillance and patient care. 2015.
    1. Saxena A, Horby P, Amuasi J, et al. Ethics preparedness: facilitating ethics review during outbreaks - recommendations from an expert panel. BMC Med Ethics. 2019;20(1):29. doi: 10.1186/s12910-019-0366-x.
    1. Nuffield Council on Bioethics . Research in global health emergencies: ethical issues. 2020.
    1. US Department of Health and Human Services Food and Drug Administration . Guidance for Industry. Influenza: developing drugs for treatment and/or prophylaxis. 2011.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner